Molecular host-virus interactions that regulate lytic reactivation of Kaposi's Sarcoma-associated Herpesvirus from latency

Molecular host-virus interactions that regulate lytic reactivation of Kaposi's Sarcoma-associated Herpesvirus from latency

Kaposi's Sarcoma-Associated Herpesvirus (KSHV; also known as Human herpesvirus-8) is a DNA tumor virus that is the etiologic agent of Kaposi's Sarcoma and other AIDS-related cancers. Epidemiologic studies have demonstrated that lytic reactivation of KSHV from latency is required for progression of these unique cancers. We are studying the critical host-virus interactions, at the molecular level, that govern reactivation of the virus, in order to gain a thorough understanding of the pathogenesis of KSHV infection.

We have previously demonstrated that a single viral protein, called Rta (for "replication and transcriptional activator"), functions as a molecular switch controlling the induction of the virus from latency. For these studies, we have developed a number of quantitative assays for measuring viral reactivation and replication in response to various proteins and stimuli. We have also determined that Rta's critical role in reactivation is to transcriptionally transactivate viral and cellular promoters in combination with other host and viral proteins. We have identified two of these cellular proteins, and we are characterizing the DNA/protein interactions that are critical for viral reactivation. We are also deciphering Rta's function by investigating its mechanisms of interaction with heterologous viral proteins. Finally, we are committed to determining the molecular regulation of progression of the viral lytic cycle in which many of the viral oncogenes are expressed.

B cell infected by KSHV and EBV in which KSHV Rta is activating expression of the EBV oncogene LMP-1. Nuclei are blue, Rta is pink, and LMP-1 is green.

Selected Publications

• Gonzalez-Lopez, O, DeCotiis, J, Goyeneche, C, Mello, H, Vicente-Ortiz, BA, Shin, HJ, Driscoll, KE, Du, P, Palmeri, D, and Lukac, DM (2019). A herpesvirus transactivator and cellular POU proteins extensively regulate DNA binding of the host Notch signaling protein RBP-Jk to the virus genome. Journal of Biological Chemistry 294: 13073-13092

• DeCotiis, JL, and DM Lukac. KSHV and the Role of Notch Receptor Dysregulation in Disease Progression. Pathogens 4:6(2017)

• DeCotiis, JL, NC Ortiz, BA Vega, and DM Lukac."An easily transfectable cell line that produces an infectious reporter virus for routine and robust quantitation of Kaposi’s sarcoma-associated herpesvirus reactivation." J. Virol Methods 247: 99-106.(2017)

• Guito, J.; Lukac, D.M. (2015) KSHV Reactivation and Novel Implications of Protein Isomerization on Lytic Switch Control. Viruses 7: 72-109. http://www.mdpi.com/1999-4915/7/1/72

• Shin, HJ, DeCotiis, J, Giron, M, Palmeri, D and DM Lukac. "Histone Deacetylase Classes I and II Regulate Kaposi's Sarcoma-Associated Herpesvirus Reactivation." J Virol 88:1281-1292.(2014).

• Guito, J, A Gavina, D Palmeri, and DM Lukac. The cellular peptidyl-prolyl cis/trans isomerase Pin1 regulates reactivation of Kaposi's sarcoma-associated herpesvirus from latency. J Virol 88:547-558. (2014).

• Guito, J, DM Lukac Kaposi's sarcoma-associated herpesvirus Rta Promoter Specification and Viral Reactivation. (Invited Review) Frontiers in Microbiology 3:30.(2012).

• Palmeri, D, Carroll, KD, Gonzalez-Lopez, O, and DM Lukac. Kaposi's sarcoma-associated herpesvirus Rta tetramers make high affinity interactions with repetitive DNA elements in the Mta promoter to stimulate DNA binding of RBP-Jk/CSL. Journal of Virology 85:11901-11915. (2011).

• Spadavecchia, S., Gonzalez-Lopez, O., Carroll KD, Palmeri, D, and DM Lukac Convergence of Kaposi's Sarcoma-Associated Herpesvirus Reactivation with Epstein-Barr Virus Latency and Cellular Growth Mediated by the Notch Signaling Pathway in Coinfected Cells, Journal of Virology 84: 10488-10500.(2010).

• Bu, W, D Palmeri, R Krishnan, R Marin, VM Aris, P Soteropoulos, and DM Lukac. Identification of Direct Transcriptional Targets of the Kaposi's sarcoma-associated herpesvirus (KSHV) Rta Lytic Switch Protein by conditional nuclear localization of Rta. Journal of Virology 82: 10709-10723. (2008).

  
  

Training and Positions

1997-2000 Postdoctoral fellow, University of California, San Francisco

present Director, GSBS-Newark Infection, Immunity, and Inflammation Track